ES2547231T3 - Polymorphic form of rotigotine - Google Patents

Abstract

A polymorphic (II) form of Rotigotine ((-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol) that has at least one of a powder X-ray diffraction spectrum comprising peaks at the following 2θº angles (+ -0.2): 12.04.13.68, 17.13, 17.72 and 19.01, measured with irradiation of Cu-Kα (1,54060 Å); a Raman spectrum comprising at least one peak at the following wave numbers (+ -3 cm -1): 226.2, 297.0, 363.9, 710.0, 737.3, 743.3, 750 , 8, 847.3, 1018.7, 1075.6, 1086.2, 1214.3, 1255.1, 1278.2, 1330.7, 1354.3 and 1448.7; a DSC peak with a Tinicio at 97 ° C + -2 ° C measured with a heating rate of 10 ° C / min; a melting point of 97 ° C + -2 ° C.

Description

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DESCRIPTION

Polymorphic form of rotigotine

Field of the Invention

The present invention relates to a new polymorphic form (form II) of Rotigotine and a method for its production, which is useful for the manufacture of a stable medicament for treating or alleviating symptoms of Parkinson's disease and other disorders related to dopamine

Technical background

Rotigotine is the international common name (INN) of the compound (-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] amino] -1-naphthaleneol having the structure shown below

image 1

Rotigotine is a non-ergolinic D1 / D2 / D3 dopamine agonist that resembles dopamine structurally and has a similar receptor profile but greater affinity for the receptor.

In contrast to ergolinic compounds, Rotigotine has a very low affinity for 5 HT2B receptors and thus a low risk of inducing fibrosis.

The actions of non-dopaminergic receptors (such as 5-HT1A agonism and A2B antagonism) may contribute to other beneficial effects, such as anti-dyskinetic activity, neuroprotective activity and antidepressant effects.

Rotigotine is described as an active agent to treat patients suffering from Parkinson's disease (described in WO 2002/089777), Parkinson plus syndrome (described in WO 2005/292331), depression (described in WO 2005 / 009424) and restless legs syndrome (described in WO 2003/092677) as well as for the treatment or prevention of the loss of dopaminergic neurons (described in WO 2005/063237).

Known pharmaceutical compositions containing Rotigotine comprise a transdermal therapeutic system (TTS) (described in WO 99/49852), a depot form (described in WO 02/15903), an iontophoretic device (described in WO 2004/050083) and an intranasal formulation (described in WO 2005/063236).

Each of the aforementioned publications is incorporated herein by reference in its entirety.

A crystalline form of Rotigotine is already known and from now on it will be designated as a polymorphic form (I). It is used, for example, as a starting material in the preparation of the matrix described in WO 2004/058247 for transdermal administration of Rotigotine.

Surprisingly, an additional crystalline form of Rotigotine (polymorphic form (II)) has now been identified and has been found to show greatly increased thermodynamic stability and improved life as well as a cubic crystalline form that represents an advantage over particulate particles. needle of the polymorphic form (I) with respect to its handling properties such as filtration properties, fluidity, electrostatic behavior, etc.

The discovery of a second crystalline polymorph of Rotigotine is especially surprising since Rotigotine is a commercial drug that has been known since the mid-eighties and has been well researched over the past decade. In addition, no indication of the presence of a second crystalline polymorph of Rotigotine was observed in a first polymorphism test that was previously performed during the development of its formulation.

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Summary of the invention

The present invention provides a new polymeric form (form II) of Rotigotine ((-) - 5,6,7,8-tetrahydro-6 [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol) .

The new polymorphic form of Rotigotine according to the present invention has at least one of the following characteristics:

a powder X-ray diffraction spectrum comprising a peak at least one of the following 2º angles (0.2): 12.04, 13.68, 17.72 and / or 19.01, measured with Cu-K radiation (1,54060 Å);

a Raman spectrum comprising at least one peak at the following wave numbers (3 cm -1): 226.2, 297.0, 363.9, 737.3, 847.3, 1018.7 and / or 1354.3;

a differential scanning calorimetry peak (DSC) with a Tinicio at 97ºC2ºC measured with a heating rate of 10ºC / min; I

a melting point of 97 ° C2 ° C

In one embodiment, the new polymorphic form of Rotigotine is characterized by two, three or four of the following powder X-ray diffraction peaks (0.2): 12.04, 13.68, 17.72, 19.01, measured with Cu-K radiation (1.54060 Å);

In one embodiment, the new polymorphic form of Rotigotine according to the invention is characterized by peaks in its Raman spectrum at wave numbers 297.0, 847.3 and 1018.7 3 cm -1.

The temperatures given here include variations of 2 ° C due to inaccuracies in the measurements, for example, of a DSC experiment. The 2 angles given here include variations of 0.2 due to inaccuracies in the measurement of dust X-ray diffraction experiments. Finally, the wave numbers given here include variations of 3 cm-1 due to inaccuracies of Raman's experiments.

The present invention also provides a pharmacological substance of Rotigotine comprising at least about 5%, more preferably at least about 10%, of the new polymorphic form of Rotigotine as defined above.

In a preferred embodiment the pharmacological substance of Rotigotine comprises at least about 50%, more preferably at least about 70%, of the new polymorphic form (II) of Rotigotine as defined above. Most preferably substantially all or all (100%) of the Rotigotine in the pharmacological substance of Rotigotine is present in the new polymorphic form (II). "Substantially all" is intended to refer to a pharmacological substance of Rotigotine comprising form II in which preferably at least 80%, more preferably at least 90%, even more preferably at least 95% of the Rotigotine is present as form (II).

In the context of the present application all percentages are given by weight unless otherwise indicated.

In addition, the present invention provides a pharmaceutical composition comprising the new polymorphic form (II) of Rotigotine as defined above and at least one pharmaceutically acceptable excipient.

The present invention also provides a process for producing the new polymorphic form (II) of Rotigotine as defined above, comprising tempering solid Rotigotine polymorphically (I) for at least 10 days at 40 ° C.

In said tempering process, the polymorphic Rotigotine (I) can be in the dry state or in the suspension state. When in a suspension state, the suspension is preferably prepared in cyclohexane or ethanol.

In another preferred embodiment of the present invention, the new polymorphic form (II) of Rotigotine as defined above is produced quantitatively by adding polymorphically shaped Rotigotine crystals (I) to the Rotigotine in suspension state obtained from the process. of temperate or ethanolic precipitation.

In another embodiment of the present invention, the new polymorphic form (II) of Rotigotine as defined above is produced quantitatively by adding polymorphic form (I) in the dry state at 40 ° C. Rotigotine crystals in polymorphic form (II). Sowing crystals of the form (II) used can be obtained from experiments of ethanolic suspension, ethanolic precipitation or other tempering process.

In another aspect of the present invention the new polymorphic form (II) of Rotigotine as defined above is used to treat a patient suffering from a disease sensitive to treatment with D2 receptor agonists.

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In various embodiments of the present invention the new polymorphic form (II) of Rotigotine as defined above is used to treat a patient suffering from Parkinson's disease, Parkinson's plus syndrome, depression, fibromyalgia or restless legs syndrome.

Brief description of the drawings

Figure 1. Experimental X-ray powder diffractogram of the new polymorphic form (II) of Rotigotine.

Figure 2. Polymeric chain (Zig-Zag) linked by H of Rotigotine molecules in crystals of new polymorphic form (II). Figure 3. Polymeric chain (Zig-Zag) linked by H of Rotigotine molecules in crystals of polymorphic form (I). Figure 4. Experimental X-ray powder diffractogram of the polymorphic form (I) of Rotigotine. Figure 5. Raman spectrum of the new polymorphic form (II) of Rotigotine. Figure 6. Superposition of the Raman spectra of the new polymorphic form (II) and the polymorphic form (I) of

Rotigotine Figure 7. DSC thermogram of the new polymorphic form (II) of Rotigotine Figure 8. DSC thermogram of the polymorphic form (I) of Rotigotine.

Detailed description of the invention

The invention relates to a new crystalline form of (-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1naphthaleneol, designated herein as form (II ). Form II differs from form I in the crystal lattice structure of (-) 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol , and the two forms give different powder X-ray diffraction diagrams (XRD), Raman spectra and differential scanning calorimetry (DSC) thermograms.

The form (I) of Rotigotine is characterized by an XRD diagram comprising a peak around 20.230.2 (2º).

The characterization of form II and distinguishing it from form I is achieved using techniques known to those skilled in the art. Specifically, the verification that form II is present can be performed using techniques such as melting point, infrared spectroscopy (IR), solid state nuclear magnetic resonance imaging (SSNMR) or Raman spectroscopy. Techniques that include differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are also useful for distinguishing polymorphs, and specifically form II from form I. One or more of the preceding techniques can be used to identify a form polymorphic of Rotigotine.

Form I and Form II have distinctive characteristic peaks in their powder X-ray diffraction diagrams as provided in Figures 1 and 4. At least one of these peaks, and preferably a majority of these peaks, will be present in The X-ray powder diffraction diagram for a given form.

In one embodiment of the invention the XRD diagram of form II exhibits a characteristic peak at 13.680.2 (2 °), in another embodiment the XRD diagram of form II exhibits a characteristic peak at 17, 720.2 (2nd) and in yet another embodiment the XRD diagram of form II exhibits a characteristic peak at 19.010.2 (2nd). Preferably, the XRD diagram of form II exhibits characteristic peaks at 13.68 and 17.72 ,20.2 (2 °). More preferably, the XRD diagram of form II may comprise peaks at 13.68, 17.72 and 19.01 ,20.2 (2 °).

The new polymorphic form (II) of Rotigotine ((-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol) is characterized by a X-ray powder diffractogram comprising peaks at one or more of 12.04, 12.32, 12.97, 13.68, 17.13, 17.72, 19.01, 20.40, 20.52, 21.84, 21.96, 22.01, 22.91 and 22.96  0.2 (2º), measured with an irradiation of Cu-K (1.54060 Å). In particular, the new polymorphic form (II) of Rotigotine is characterized by at least one of the following powder X-ray diffraction peaks: 1,204, 13.68, 17.72, and 19.01  0.2 ( 2nd), measured with an irradiation of Cu-K (1,54060 Å) (Figure 1).

The comparison of the crystalline network between the new polymorphic form (II) and the polymorphic form (I) (Figures 2 and 3) shows that the main intermolecular hydrogen bonds are similar in both cases:

image2

However, a drastic conformational difference is observed for the torsion angle of the thiophene ring with 5

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with respect to the adjacent CH2-CH2 chain. It is this difference of approximately 100 ° (torsion angle) between the two conformational polymorphs that leads to denser packaging and a change in crystal symmetry.

The results of the comparison of the crystalline network are summarized in the following table:

Form (I)

Form (II)

Crystalline system

Tetragonal orthorhombic

Space group

P43 P212121

Unit cell dimensions

Cell length [Å *] a 8,2030 (10) b 8,2030 (10) c 26,899 (5) a 8.4310 (10) b 13.620 (2) c 14.868 (2)

Cell angle [*]

α 90 β 90  90 α 90 β 90  90

Cellular volume [Å3]

1810.01 1707.3

Z: 4 Z ’: 0

Z: 4 Z ’: 0

Density (calculated) [g / cm3]

1,158 1,227

These results are supported by the different solubility of the two polymorphs in EtOH. The solubility at room temperature of the polymorphic form (I) of Rotigotine in EtOH is about 500 mg / ml (1: 2 [weight / weight]), while the solubility of the new polymorphic form (I) of Rotigotine in EtOH is about 60100 mg / ml (0.6-1: 10 [weight / weight]), that is, the solubility of the new polymorphic form (II) of Rotigotine in EtOH is at least five times lower than the solubility of the polymorphic form (I) of Rotigotine in EtOH.

The crystallographic differences between the two polymorphic forms of Rotigotine become more evident when their X-ray diffractograms are compared as shown in Figs. 1 and 4

The new polymorphic form (II) of Rotigotine can also be characterized by its Raman spectrum (Figure. 5).

In addition, differential scanning calorimetry (DSC) data reveal the difference between the two polymorphic forms of Rotigotine (Figures 7 and 8). Basically, the new polymorphic form (II) of Rotigotine exhibits both a higher melting point and a higher enthalpy of fusion, and by applying the Burger-Ramberger rules, it could be affirmed that form (II) is thermodynamically more stable than the form (I) at any temperature considered. Therefore, the two Rotigotine polymorphs appear to be monotropically related.

The polymorphic form (II) of Rotigotine can be further characterized and distinguished from the form (I) by differential scanning calorimetry (DSC). A DSC thermogram of the form (II) is provided in the figure. 7, and was obtained using DSC techniques known to those skilled in the art. One skilled in the art would easily be able to determine the conditions necessary to obtain a DSC thermogram of the form (II). Several differential scanning calorimeters are available to those skilled in the art and include the Mettler Toledo differential scanning calorimeter (DSC822e) which uses temperatures from about 25 ° C to 250 ° C, in particular from about 30 ° C to about 140 ° C and the temperature is increased at various speeds that include 1ºC / min, 10ºC / min, 20ºC / min, among other instruments and conditions. One skilled in the art would recognize that the positions of the peaks in the DSC thermogram may vary depending on kinetic factors such as, for example, heating rate and particle size.

The DSC thermogram of form (II) differs from the DSC thermogram of form (I) and includes a peak with a Tinicio of about 97 ° C ± 2 ° C. The DSC thermogram of form (I) differs from the DSC thermogram of form (II) and includes a peak with a Tinicio of about 77 ° C ± 2 ° C

The new polymorphic form (II) of Rotigotine can be prepared by the following procedures. In these procedures, "Rotigotine" means the free base, ie (-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] -amino] 1- naphthalenol

The new polymorphic form (II) of Rotigotine can be illustratively prepared by the following procedures.

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(i) The preparation of the new polymorphic form (II) of Rotigotine by tempering comprises:

-Place Rotigotine polymorphically (I) in an Aluthene bag

-Seal and store the bag at 38-40ºC for 10 days.

(ii) The preparation of the new polymorphic form (II) of Rotigotine from an ethanolic suspension comprises:

-suspend Rotigotine polymorphically (I) in ethanol

- shake for 2 h at 50 to 150 rpm

- optionally add to the polymorphic rotigotine ethanolic suspension (I) polymorphic rotigotine (II)

- shake for another 24 h at 50 to 150 rpm at room temperature

-filtration of the suspension

-Rotigotine drying of the polymorphic form (I) to constant weight.

The crystalline form of Rotigotine can be prepared substantially as a single polymorph, for example, comprising more than 95% of the form (II), or it can be crystallized in combination with the form (I) or other polymorphs. In some embodiments, the crystalline form of Rotigotine comprises at least 50% of the form (II). In some embodiments, the crystalline form of Rotigotine comprises at least 70% of the form (II). In some embodiments, the crystalline form of Rotigotine comprises at least 80% of the form (II). In yet other embodiments, the crystalline form of Rotigotine comprises at least 90% of the form (II).

The polymorphic form (II) of Rotigotine can be used as a therapeutic active substance.

When Rotigotine is used in the new polymorphic form (II) to treat a patient suffering from a disease sensitive to treatment with dopamine D1 / D2 / D3 agonists, particularly D2 receptor agonists, it can be administered orally or parenterally. In general, it is administered parenterally, for example, in the form of a transdermal therapeutic system (TTS), by injection, such as in the form of a depot suspension, by means of an iontophoretic device or in the form of an intranasal formulation.

The diseases that are generally treated with Rotigotine in the new polymorphic form (II) are Parkinson's disease, Parkinson's plus syndrome, depression, fibromyalgia and restless legs syndrome. The respective dose will vary depending on the symptoms, age, sex, weight and sensitivity of the patients, the method of administration, the time and intervals of administration and pharmaceutical preparations, etc. Therefore, there is no particular limitation regarding the dose.

Pharmaceutical preparations containing the new polymorphic form (II) of Rotigotine as transdermal therapeutic systems, injections or tablets, etc., are prepared according to methods commonly known in the state of the art.

The invention and the best way to carry it out will be explained in more detail in the following non-limiting examples.

Examples

[Preparation]

Preparation Example 1

A sample of the polymorphic form (I) of Rotigotine, lot 16208652, was placed in a small Aluthene® bag (2006 manufacture Bischoff + Klein). The sample was sealed and stored at 38-40 ° C for 10 days. After this incubation time 1 g of the sample was dissolved in 2 g of EtOH, after which a heavy precipitation of form II occurred.

Preparation Example 2

5,277 kg of the polymorphic form (I) of rotigotine (lot SPM 5904) were loaded into a 20 l plastic bottle and converted with 5.3 l of EtOH in an ethanolic suspension. The suspension was transferred to a nitrogen flow reactor and the plastic bottle was washed with 8.1 l more EtOH. The washing liquid was also transferred to the reactor and the resulting suspension was stirred for 24 h at 75 rpm at room temperature. Subsequently, the crystalline suspension was discharged from the reactor via a glass suction filter. The reactor was washed with 2.6 L of EtOH and then the washing liquid was used to wash the filtrate obtained. Finally, the filtrate was transferred to four heavy metal sheets and dried for 43 h at 40 ° C to constant weight.

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In both examples, the successful formation of Rotigotine in the polymorphic form (II) was confirmed by analytical data from DSC and XRD.

In addition, polymorphic form (I) of rotigotine could be quantitatively transformed into polymorphic form (II) of Rotigotine in a procedure according to preparation example 2, when to the ethanolic suspension of polymorphic form (I), seeds of Rotigotine of the polymorphic form (II).

[Characterization of the new polymorphic form (II) of Rotigotine compared to the polymorphic form (I) of Rotigotine]

X-ray diffraction of a single crystal

Individual crystals suitable for diffraction have been obtained by rapidly evaporating a methanol solution of reference batch 7769396 of the polymorphic form (II) of Rotigotine. The monocrystalline X-ray diffraction data (Oxford Gemini R Ultra, Mo-Kα irradiation (0.71073 Å)) are the following: C19H25NOS, M = 315.46, Orthorhombic P 212121, a = 8.4310 (10 ) Å, b = 13,620 (2) Å, c = 14,868 (2) Å, α = β = γ 90º, V [Å3] = 1707.3, Z = 4, Dc [g / cm3] = 1,227, λ = 1.54178 Å. The final disagreement factor R is 4%.

The cohesive forces of the crystalline packing of the polymorphic form (II) of Rotigotine are mainly formed by zigzag polymer chains of hydrogen bonds via the basic nitrogen atom (N1) and the phenol oxygen (O1).

This determination of the structure confirms that the polymorphic form (II) is a true Rotigotine polymorph and confirms the appearance of conformational polymorphism.

The determination of the structure of the polymorphic form (II) of Rotigotine allows to simulate a theoretical powder X-ray pattern (Mercury 1.5) characterized by the following peaks: 8.82, 12.06, 12.34, 13, 13, 7, 14.32, 17.18, 17.76, 19.04, 20.44, 22.06, 23.02, 24.26 and 27.76 (° 2θ).

X-ray diffraction of experimental powder

The X-ray analysis was performed in a STOE STADI-P powder diffraction system with an irradiation of Cu-Kα (1,54060 Å), in which the experimental pattern of the polymorphic (II) form of Rotigotine was shown It matches perfectly with its simulated dust pattern.

According to embodiments of the invention, the XRD patterns of form (I) and form (II) contain peaks that are specific to each form. The XRD pattern of form (II) contains peaks that are not present in the XRD pattern of form (I), and includes a peak at about 17.72 ± 0.2 (° 2θ). In another embodiment, the XRD pattern of form (II) differs from the XRD pattern of form (I) and includes a peak at about 13.68 ± 0.2 (° 2θ). In another embodiment, the XRD pattern of form (II) differs from the XRD pattern of form (I) and includes a peak at about 19.01 ± 0.2 (° 2θ). In another embodiment, the XRD pattern of form (II) differs from the XRD pattern of form (I) and includes peaks at about 17.72 ± 0.2 (° 2θ) and 19.01 ± 0.2 ( 2θ). Importantly, the XRD pattern of the form

(II) lacks a peak at around 20.23 ± 0.2 (° 2θ).

The results also clearly demonstrate the difference between the two polymorphs of Rotigotine. (Figures 1 and 4). The experimental X-ray diffraction pattern of the new polymorphic (II) form of Rotigotine is characterized by peaks at diffraction angles (2θº) of 12.04, 12.32, 12.97, 13.68, 17.72, 19.01, 20.40, 20.52, 21.84, 21.96, 22.01, 22.91 and 22.96, while the experimental pattern of the polymorphic form (I) is characterized by peaks at angles diffraction (2nd) of 10.83, 12.68, 14.66, 15.32, 16.66, 16.68, 20.23, 22.67, 25.17, 25.47, 26.27, 27.75 and 29.55. Each of these peaks, either alone or in combination with others, can be taken as the basis for characterizing Rotigotine of form (I) or form (II), respectively.

Raman spectroscopy

A sample of Rotigotine was placed on a glass cover and then, based on only one crystal, the sample was focused with 10x and 50x-WD: Raman HJY ARAMIS, laser of 784.9 nm, 4 × 20 s, obj. 10x + 50x-WD, 500 µm hole, 100 µm slit. The acquisition was made in 4 × 20 seconds with the 50x-WD objective.

The results are shown in the Figures. 5 and 6. Figure 5 represents the spectrum of the polymorphic form (II) of Rotigotine while figure 6 shows the superposition of lots 7769396 (polymorphic form (II) of reference) and WE 11664 PS-7 (predominantly polymorphic form (I)). This overlay highlights several discriminative peaks of these two lots. The new polymorphic form (II) of Rotigotine comprises at least one peak, preferably at least two peaks, at least three or at least four peaks at selected wave numbers (cm-1) of 226.2, 297, 0, 363.9, 710.0, 737.3, 743.3, 750.8, 847.3, 878.3, 1018.7, 1075.6, 1086.2, 1214.3, 1255.1, 1278.2, 1330.7, 1354.3 and 1448.7 ± 3 cm-1, while the polymorphic form (I) has characteristic peaks at wave numbers (cm-1) of 238.4, 277.3, 307.6, 445.9, 682.6, 747.2, 882.2, 1027.2, 1039.4, 1081.6 and 1324.3 ± 3 cm -1. The new polymorphic form (II) of Rotigotine ((-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol) is characterized by a Raman spectrum comprising at least one peak, preferably at least two, per

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at least three or at least four peaks at wave numbers (cm-1) selected from 710.0, 737.3, 743.3, 847.3, 1018.7, 1214.3, 1278.2, 1354 , 3 ± 3 cm-1. In particular, the new polymorphic form (II) of Rotigotine is characterized by at least one of the following peaks: 226.2, 297.0, 363.9, 737.3, 847.3, 1018.7 and 1354.3 ± 3 cm

one

.

5 Differential scanning calorimetry (DSC)

Rotigotine thermal behavior investigations of polymorphic form (I) (lot 1608726) and polymorphic form (II) (lot 7769396) were carried out in a Mettler Toledo DSC system and in a TA instrument (Q-1000). The analyzes were carried out with a heating rate of 10 ° C / min in perforated aluminum crucibles in a temperature range of 30 ° C to 140 ° C.

10 The results are summarized in the figure. 7 and Figure 8. The DSC thermogram of the new polymorphic form (II) exhibits an endothermic peak with a Tinicio at 97º ± 2ºC and a Tpico at 98ºC ± 2ºC, while the appearance of the endothermic peak of the polymorphic form (I ) is at 77º ± 2ºC under the same conditions. For both polymorphs, only one peak could be observed in their thermograms, indicating that said polymorphs were free of any impurity of the respective other polymorph, with respect to the sensitivity of DSC.

In summary, the two polymorphic forms of Rotigotine can be distinguished by their respective melting point and their respective enthalpy of fusion. Both are larger for the new polymorphic form (II) and by applying the Burger-Ramberger rules, it could be shown that the polymorphic form (II) is thermodynamically more stable than the polymorphic form (I) at all temperatures considered. Therefore, the two polymorphs of Rotigotine are most likely monotropically related.

20 The melting point of the new polymorphic form (II) of Rotigotine can also be measured with the capillary method (in a water / oil bath with a magnifying glass) or with a Kofler Hotbench.

Claims (14)

5 10 fifteen twenty 25 30 35 40 1. A polymorphic (II) form of Rotigotine ((-) - 5,6,7,8-tetrahydro-6- [propyl [2- (2-thienyl) ethyl] -amino] -1-naphthaleneol) at least one of an X-ray powder diffraction spectrum comprising peaks at the following 2º angles (0.2): 12.04, 13.68, 17.13, 17.72 and 19.01, measured with irradiation of Cu-K (1,54060 Å); a Raman spectrum comprising at least one peak at the following wave numbers (3 cm -1): 226.2, 297.0, 363.9, 710.0, 737.3, 743.3, 750, 8, 847.3, 1018.7, 1075.6, 1086.2, 1214.3, 1255.1, 1278.2, 1330.7, 1354.3 and 1448.7; a DSC peak with a Tinicio at 97 ° C2 ° C measured with a heating rate of 10 ° C / min; a melting point of 97 ° C2 ° C.

2.

A polymorphic form of Rotigotine that has a powder X-ray diffraction spectrum measured with irradiation of Cu-K (1,54060 Å) substantially as shown in Figure 1.

3.

A pharmacological substance of Rotigotine comprising at least 5% of a polymorphic form of Rotigotine as defined in any one of claims 1-2.

Four.

A pharmacological substance of Rotigotine comprising at least 50% of a polymorphic form of Rotigotine as defined in any one of claims 1-2.

5.

A pharmacological substance of Rotigotine comprising at least 90% of a polymorphic form of Rotigotine as defined in any one of claims 1-2.

6.

A pharmacological substance of Rotigotine comprising at least 95% of a polymorphic form of Rotigotine as defined in any one of claims 1-2.

7.

A pharmacological substance of Rotigotine according to any of claims 3-6 for use as a therapeutic active substance.

8.

A crystalline polymorph according to any one of claims 1 to 2 for use as a therapeutic active substance.

9.

The use of the polymorphic form of Rotigotine as defined in any one of claims 1-2 or of the pharmacological substance of Rotigotine according to claims 3-6 and at least one pharmaceutically acceptable excipient in a method for the production of a composition Pharmaceutical

10.

The use according to claim 9, wherein the pharmaceutical composition is in the form of a transdermal therapeutic system.

eleven.

The method for the production of a pharmaceutical composition using the polymorphic form of Rotigotine as defined in any one of claims 1-2 or the pharmacological substance of Rotigotine according to claims 3-6 and at least one pharmaceutically acceptable excipient.

12.

The method according to claim 11, wherein the pharmaceutical composition is in the form of a transdermal therapeutic system.

13.

A polymorphic form of Rotigotine as defined in any one of claims 1-2 or a pharmacological substance of Rotigotine according to claims 3-6 for use in a method of treating a patient suffering from a dopamine-related disorder, wherein such disorder is selected from Parkinson's disease, Parkinson's plus syndrome, depression, fibromyalgia and / or restless legs syndrome.

14.

The use of a polymorphic form of Rotigotine as defined in any of claims 1-2 or of the pharmacological substance of Rotigotine according to claims 3-6 for the manufacture of a medicament for the treatment of a patient suffering from a disorder related to Dopamine, in which the dopamine-related disorder is selected from Parkinson's disease, Parkinson's plus syndrome, depression, fibromyalgia and / or restless legs syndrome.

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